Alpha-2 adrenergic receptors mediate several important functions of the endogenous catecholamines in both the central and peripheral nervous systems. Several clinically important drugs appear to produce their pharmacologic effects through an interaction at alpha-2 receptors. There now exists considerable evidence indicating significant differences in the pharmacological characteristics and regulation of mammalian alpha-2 adrenergic receptors from various tissues and species. We suggest that differences in the pharmacological properties and in the regulation (mechanism of action) of alpha-2 adrenergic receptors may be due to differences in the structure of the alpha-2 adrenergic receptor complex. To test this hypothesis, it is proposed to compare in various tissues and species: (1) The rank order and relative potencies of various adrenergic drugs using both radioligand binding and functional assays; (2) The thermal stability and pH optima of radioligand binding; (3) The functional size of the receptor complex using target analysis (radiation inactivation); (4) The apparent molecular size determined by gel filtration and sucrose density gradient centrifugation of receptor preparations solubilized in the presence and absence of agonist; and (5) The apparent molecular weight from SDS gel electrophoresis of partially purified receptors labeled with a photoaffinity probe. These studies should help to resolve the present confusion in classification of alpha receptors and may lead to more selective alpha adrenergic drugs for clinical use.